ABSTRACT
Effective treatments against Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Monoclonal antibodies have shown promising results in patients. Here, we evaluate the in vivo prophylactic and therapeutic effect of COVA1-18, a neutralizing antibody highly potent against the B.1.1.7 isolate. In both prophylactic and therapeutic settings, SARS-CoV-2 remains undetectable in the lungs of treated hACE2 mice. Therapeutic treatment also causes a reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg-1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 shows very strong antiviral activity in the upper respiratory compartments. Using a mathematical model, we estimate that COVA1-18 reduces viral infectivity by more than 95% in these compartments, preventing lymphopenia and extensive lung lesions. Our findings demonstrate that COVA1-18 has a strong antiviral activity in three preclinical models and could be a valuable candidate for further clinical evaluation.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Neutralizing/administration & dosage , Antiviral Agents/administration & dosage , COVID-19 Drug Treatment , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/genetics , Animals , Antibodies, Monoclonal/pharmacokinetics , Antiviral Agents/pharmacokinetics , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Humans , Lung/metabolism , Lung/virology , Macaca fascicularis , Male , Mesocricetus , Mice , Mice, Transgenic , SARS-CoV-2/isolation & purification , Tissue Distribution , Viral LoadABSTRACT
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is continuing to disrupt personal lives, global healthcare systems, and economies. Hence, there is an urgent need for a vaccine that prevents viral infection, transmission, and disease. Here, we present a two-component protein-based nanoparticle vaccine that displays multiple copies of the SARS-CoV-2 spike protein. Immunization studies show that this vaccine induces potent neutralizing antibody responses in mice, rabbits, and cynomolgus macaques. The vaccine-induced immunity protects macaques against a high-dose challenge, resulting in strongly reduced viral infection and replication in the upper and lower airways. These nanoparticles are a promising vaccine candidate to curtail the SARS-CoV-2 pandemic.
Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Macaca fascicularis , Spike Glycoprotein, Coronavirus/chemistry , Animals , Antibodies, Neutralizing , B-Lymphocytes/immunology , COVID-19/immunology , COVID-19/prevention & control , Mice , Mice, Inbred BALB C , Models, Animal , Nanoparticles/administration & dosage , Rabbits , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/blood , T-Lymphocytes/immunology , Viral LoadABSTRACT
Most antibodies isolated from individuals with coronavirus disease 2019 (COVID-19) are specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here, we determined a crystal structure of the COVA1-16 antibody fragment (Fab) with the SARS-CoV-2 receptor-binding domain (RBD) and negative-stain electron microscopy reconstructions with the spike glycoprotein trimer to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long complementarity-determining region (CDR) H3, and competes with the angiotensin-converting enzyme 2 (ACE2) receptor because of steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with the structural and functional rationale for epitope conservation, provide insights for development of more universal SARS-like coronavirus vaccines and therapies.
Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Viral/metabolism , COVID-19 Vaccines/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Severe acute respiratory syndrome-related coronavirus/immunology , Antibodies, Viral/genetics , Broadly Neutralizing Antibodies/genetics , Broadly Neutralizing Antibodies/metabolism , Conserved Sequence/genetics , Cross Reactions , Crystallization , Epitope Mapping , Epitopes, B-Lymphocyte/genetics , Epitopes, B-Lymphocyte/metabolism , Humans , Immunoglobulin Fab Fragments/genetics , Immunoglobulin Fab Fragments/metabolism , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs/geneticsABSTRACT
Most antibodies isolated from COVID-19 patients are specific to SARS-CoV-2. COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here we determined a crystal structure of COVA1-16 Fab with the SARS-CoV-2 RBD, and a negative-stain EM reconstruction with the spike glycoprotein trimer, to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long CDR H3, and competes with ACE2 binding due to steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with structural and functional rationale for the epitope conservation, provide a blueprint for development of more universal SARS-like coronavirus vaccines and therapies.
ABSTRACT
The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a large impact on global health, travel, and economy. Therefore, preventative and therapeutic measures are urgently needed. Here, we isolated monoclonal antibodies from three convalescent coronavirus disease 2019 (COVID-19) patients using a SARS-CoV-2 stabilized prefusion spike protein. These antibodies had low levels of somatic hypermutation and showed a strong enrichment in VH1-69, VH3-30-3, and VH1-24 gene usage. A subset of the antibodies was able to potently inhibit authentic SARS-CoV-2 infection at a concentration as low as 0.007 micrograms per milliliter. Competition and electron microscopy studies illustrate that the SARS-CoV-2 spike protein contains multiple distinct antigenic sites, including several receptor-binding domain (RBD) epitopes as well as non-RBD epitopes. In addition to providing guidance for vaccine design, the antibodies described here are promising candidates for COVID-19 treatment and prevention.